Donepezil transdermal delivery system

ABSTRACT

A transdermal delivery system for systemic delivery of donepezil is described, where the system comprises an adhesive matrix drug reservoir layer comprised of a copolymer of acrylic acid/vinyl acetate, triethyl citrate, and donepezil base generated in situ by reaction of donepezil HCl and an alkaline salt. The system is provided for treatment of Alzheimer&#39;s disease, and achieves transdermal delivery of the therapeutic agent at steady state that is bioequivalent to administration of the therapeutic agent orally.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.15/660,939, filed Jul. 26, 2017, pending, which claims the benefit ofU.S. Provisional Application No. 62/504,408, filed May 10, 2017; U.S.Provisional Application No. 62/504,391, filed May 10, 2017; U.S.Provisional Application No. 62/457,794, filed Feb. 10, 2017; U.S.Provisional Application No. 62/444,763, filed Jan. 10, 2017; U.S.Provisional Application No. 62/444,745, filed Jan. 10, 2017; U.S.Provisional Application No. 62/423,133, filed Nov. 16, 2016; U.S.Provisional Application No. 62/367,542, filed Jul. 27, 2016; and U.S.Provisional Application No. 62/367,502, filed Jul. 27, 2016, eachincorporated herein by reference in its entirety.

TECHNICAL FIELD

The subject matter described herein relates to a transdermal deliverysystem manufactured with a donepezil salt for systemic delivery ofdonepezil.

BACKGROUND

Donepezil is an acetylcholinesterase inhibitor with the chemicalstructure2,3-Dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one:

Donepezil has a molecular weight of 379.5 and is lipophilic (LogP value3.08-4.11).

An oral tablet of donepezil hydrochloride)(ARICEPT® is approved in theU.S. for use in treating Alzheimer's dementia. Due to the nature ofcognitive disorders, oral medications may be subject to problems withpatient compliance especially for formulations that need to be takenthroughout the day. Delivery of medications by transdermal, injection,or rectal routes to patients suffering from cognitive disorders has beeninvestigated. U.S. Pat. No. 7,858,114 describes a percutaneousabsorption preparation of donepezil for use as a plaster for long termdelivery of an anti-dementia drug. U.S. Patent No. 2014/0370076describes a transdermal drug delivery system comprising donepezil or asalt thereof that uses an acrylate-rubber hybrid adhesive that isprepared by a process without n-hexane. U.S. Pat. No. 4,895,841 to EisaiCo., Ltd. describes cyclic amine compounds including donepezil for usein treating dementia including Alzheimer senile dementia, Huntington'schorea, Pick's disease, and ataxia. Other transdermal delivery systemsproposed use an overlay or other rate-limiting membrane to controldelivery of the drug from the transdermal device, see e.g. U.S.Published Application No. 2010/0178307 which describes the use of afirst and second overlay. Despite these teachings, there are nodonepezil transdermal patches or devices available in the United States.

Delivery of anti-dementia drugs over a long period of time (e.g. severaldays or more) is difficult. Transdermal delivery of basic drugsincluding donepezil can be especially difficult due to poor skinpermeability. Further, some active agents have poor or low solubility inthe adhesives and/or other components used in typical transdermalformulations. Further, there is a need for stable, long termadministration of anti-dementia agents (e.g. 1-10 days or more) thatprovides a stable and effective release of the agent over theadministration period and has suitable adhesion for the long termadministration.

Therefore, there exists a need for transdermal compositions, devices andmethods that address these shortcomings.

The foregoing examples of the related art and limitations relatedtherewith are intended to be illustrative and not exclusive. Otherlimitations of the related art will become apparent to those of skill inthe art upon a reading of the specification and a study of the drawings.

BRIEF SUMMARY

The following aspects and embodiments thereof described and illustratedbelow are meant to be exemplary and illustrative, not limiting in scope.

In one aspect, a transdermal delivery system for systemic delivery ofdonepezil is provided. The system comprises a skin contact adhesivelayer to attach the system to the skin of a user, and a drug reservoircomprised of (i) a solvent composition comprising glycerin and one ormore of lauryl lactate, sorbitan monolaurate and triethyl, and (ii)donepezil base generated in situ by reaction of donepezil HCl and analkaline salt. In one embodiment, the drug reservoir further comprisesan acrylate copolymer.

In one embodiment, the system further comprises an intermediate layerthat, in one embodiment, is directly on the contact adhesive layer anddisposed between the contact adhesive layer and the drug reservoir. Inone embodiment, the intermediate layer is a microporous membranecomprising a plurality of pores. In another embodiment, the plurality ofpores in the microporous membrane contains a solvent compositioncomprised of one or more of triethyl citrate, sorbitan monolaurate, andlauryl lactate.

In another aspect, a transdermal delivery system for systemic deliveryof donepezil is provided. The system comprises, in series from the skinfacing side to the external environment, a skin contact adhesive layerto attach the system to the skin of a user, the skin contact adhesivelayer optionally manufactured from an adhesive formulation that does notcomprise donepezil base or a donepezil salt. Directly in contact withthe skin contact adhesive layer is an intermediate layer. On theopposing surface of the intermediate layer is a drug reservoir layercomprised of glycerin, and donepezil base generated in situ by reactionof donepezil HCl and an alkaline salt.

In one embodiment, the drug reservoir additionally comprises a copolymerof acrylic acid/vinyl acetate.

In other embodiments, the transdermal system additionally comprises afirst backing layer, and in contact with the first backing layer is anadhesive overlay. A second backing layer may be in contact with theadhesive overlay and with the environment.

In one embodiment, the skin contact adhesive layer is comprised of acopolymer of acrylic acid/vinyl acetate.

In another embodiment, the skin contact adhesive layer additionallycomprises crosslinked polyvinylpyrrolidone.

In yet another embodiment, the skin contact adhesive layer comprises askin contact adhesive layer solvent composition that comprises one ormore solvents selected from the group consisting of triethyl citrate,sorbitan monolaurate, and lauryl lactate. In still another embodiment,contact adhesive layer solvent composition comprises at least two oftriethyl citrate, sorbitan monolaurate, and lauryl lactate. In anotherembodiment, the contact adhesive layer solvent composition comprisestriethyl citrate, sorbitan monolaurate, and lauryl lactate.

In one embodiment, the intermediate layer is a rate controlling membranefor donepezil base.

In another embodiment, the rate controlling membrane is a microporouspolypropylene.

In yet another embodiment, the intermediate layer is a non-wovenpolyester.

In one embodiment, the alkaline salt in the drug reservoir layer issodium bicarbonate.

In another embodiment, the drug reservoir layer additionally comprisestriethyl citrate.

In still another embodiment, the drug reservoir layer additionallycomprises one or both of sorbitan monolaurate and lauryl lactate.

In yet another embodiment, the adhesive overlay is comprised of apolyisobutylene and polybutene mixture. In another embodiment,embodiment, the adhesive overlay is comprised of a single layer or asingle-ply layer of an acrylate adhesive.

In one embodiment, the adhesive overlayer is comprised of a first layerand a second layer, the first layer composed of a polyisobutylene,polybutene and crosslinked polyvinylpyrrolidone mixture and the secondlayer composed of an acrylic adhesive.

In another aspect, a composition comprising (i) donepezil base generatedin situ by reaction of donepezil HCl and an alkaline salt; (ii) glycerin(glycerol) and, optionally, (iii) a copolymer of acrylic acid/vinylacetate, is provided.

In one embodiment, the drug reservoir comprises triethyl citrate.

In another embodiment, the drug reservoir comprises sorbitanmonolaurate.

In still another embodiment, the drug reservoir comprises a crosslinkedpolyvinylpyrrolidone.

In yet another embodiment, the alkaline salt is selected from the groupconsisting of sodium carbonate, sodium bicarbonate, potassium carbonate,potassium bicarbonate, trisodium phosphate, disodium hydrogen phosphate,sodium oxylate, sodium succinate, sodium citrate, and sodium salicylate.

In another aspect, a composition consisting essentially of donepezilbase generated in situ by reaction of donepezil HCl and sodiumbicarbonate; a permeation enhancer mixture of triethyl citrate, sorbitanmonolaurate, and glycerin; and a polymeric, adhesive matrix ofcrosslinked polyvinylpyrrolidone and a copolymer of acrylic acid/vinylacetate is provided.

In yet another aspect, a composition consisting essentially of donepezilbase generated in situ by reaction of between about 5-25 wt % donepezilHCl and between about 1-5 wt % sodium bicarbonate; about 0-15 wt %triethyl citrate; about 0-5 wt % sorbitan monolaurate; about 5-15 wt %glycerin; about 1-10 wt % lauryl lactate; about 5-25 wt % crosslinkedpolyvinylpyrrolidone; and about 30-50 wt % acrylate-vinylacetatecopolymer is provided.

In yet another aspect, a composition consisting essentially of donepezilbase generated in situ by reaction of between about 10-25 wt % donepezilHCl and between about 1-5 wt % sodium bicarbonate; about 5-15 wt %triethyl citrate; about 0.5-5 wt % sorbitan monolaurate; about 5-15 wt %glycerin; about 1-10 wt % lauryl lactate; about 5-25 wt % crosslinkedpolyvinylpyrrolidone; and about 30-50 wt % acrylate-vinylacetatecopolymer is provided.

In still another aspect, a composition consisting essentially ofdonepezil base generated in situ by reaction of between about 14-18 wt %donepezil HCl and between about 2-5 wt % sodium bicarbonate; about 8-12wt % triethyl citrate; about 1.5-2.5 wt % sorbitan monolaurate; about9-11 wt % glycerin; about 1-10 wt % lauryl lactate; about 13-17 wt %crosslinked polyvinylpyrrolidone; and about 40-42 wt %acrylate-vinylacetate copolymer is provided.

In still another aspect, a composition consisting essentially ofdonepezil base generated in situ by reaction of between about 10-18 wt %donepezil HCl and between about 1-5 wt % sodium bicarbonate; about 8-12wt % triethyl citrate; about 1.5-2.5 wt % sorbitan monolaurate; about9-11 wt % glycerin; about 1-10 wt % lauryl lactate; about 13-17 wt %crosslinked polyvinylpyrrolidone; and about 40-42 wt %acrylate-vinylacetate copolymer is provided.

In yet another aspect, a transdermal device or a composition iscomprised of the compositions as described herein, a rate controllingmembrane or a non-woven layer; and a skin contact adhesive is provided.

In one embodiment, the rate controlling membrane is a microporouspolypropylene membrane.

In one embodiment, the microporous membrane has a plurality of pores,where the plurality of pores contains a solvent composition comprised ofone or more of triethyl citrate, sorbitan monolaurate, and lauryllactate.

In another embodiment, a skin contact adhesive comprises triethylcitrate, an α-hydroxy acid, or both.

In yet another embodiment, the α-hydroxy acid is an ester of lactic acidor glycolic acid.

In one embodiment, the α-hydroxy acid is lauryl lactate.

In another aspect, a method for treating Alzheimer's disease isprovided, wherein a transdermal delivery system or a composition or asystem comprising a composition as described herein is provided foradministration to the skin of a patient.

In another aspect, a method for delivering a therapeutic agent to asubject is provided, the method comprising providing a transdermaldelivery system as described herein or a transdermal delivery systemcomprising a composition as described herein, and administering orinstructing to administer the transdermal delivery system to the skin ofa subject. The administering achieves transdermal delivery of thetherapeutic agent that is bioequivalent to administration of thetherapeutic agent orally, wherein bioequivalency is established by (a) a90% confidence interval of the relative mean Cmax and AUC of thetherapeutic agent administered from the transdermal delivery system andvia oral delivery between 0.70 and 1.43 or between 0.80 and 1.25, or (b)a 90% confidence interval of the geometric mean ratios for AUC and Cmaxof the therapeutic agent administered from the transdermal deliverysystem and via oral delivery between 0.70 and 1.43 or between 0.80 and1.25.

In one embodiment, bioequivalency is established in healthy subjects.

In another embodiment, bioequivalency is established in a fastingcondition. In one embodiment, bioequivalency is established in a fed ornon-fasting condition.

In still another embodiment, bioequivalency is established using thesame dose of therapeutic agent given orally and transdermally. Inanother embodiment, the dose of therapeutic agent given transdermally iswithin about 5%, 10%, or 15% of the dose given orally.

In yet another embodiment, the chronic condition is Alzheimer's disease.

In still another embodiment, the administering or instructing toadminister comprises administering or instructing to administer onceweekly.

In an embodiment, the transdermal delivery system comprises a dose ofdonepezil base to provide between 0.05-25 mg/24 hours, 0.1-25mg/24hours, 1-25 mg/24 hours or between 5-10 mg/24 hours.

In addition to the exemplary aspects and embodiments described above,further aspects and embodiments will become apparent by reference to thedrawings and by study of the following descriptions.

Additional embodiments of the present systems, methods and compositions,and the like, will be apparent from the following description, drawings,examples, and claims. As can be appreciated from the foregoing andfollowing description, each and every feature described herein, and eachand every combination of two or more of such features, is includedwithin the scope of the present disclosure provided that the featuresincluded in such a combination are not mutually inconsistent. Inaddition, any feature or combination of features may be specificallyexcluded from any embodiment of the present invention. Additionalaspects and advantages of the present invention are set forth in thefollowing description and claims, particularly when considered inconjunction with the accompanying examples and drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1D are illustrations of transdermal delivery systems accordingto several embodiments;

FIG. 2A is a graph of mean plasma concentration of donepezil, in ng/mL,as a function of time, in days, in human subjects treated with adonepezil transdermal delivery system (circles) for 1 week, or with 5 mgof donepezil administered orally on day 1 and on day 7 (triangles);

FIG. 2B is a graph showing the mean plasma concentration of donepezil,in ng/mL, in the 24 hour period after oral administration of a 5 mgdonepezil tablet (triangles) and after removal of the donepeziltransdermal delivery system (circles);

FIG. 3 is a graph showing the projected mean plasma concentration ofdonepezil, in ng/mL, in the last week of a 28 day (4 week) treatmentperiod with a transdermal delivery system designed to administer 10mg/day for a week (solid line), with a new patch applied once weekly,and over a 28 day period with a 10 mg daily oral tablet of donepezil(dashed line);

FIG. 4 is a bar graph of the number of subjects in the group treatedwith the donepezil transdermal delivery system for 1 week and theobserved skin irritation subsequent to patch removal, where the openbars indicate no skin irritation and the filled bars indicate mild skinirritation;

FIG. 5A shows the mean plasma concentration of donepezil, in ng/mL, ateach day in week 5 of a clinical human study where subjects were treatedwith donepezil administered transdermally from transdermal patch with afirst surface area (solid line) and a second, larger surface area(dashed line) and donepezil administered orally, where the donepezilplasma concentration for patients treated orally is indicated by thethick, bold line at days 6-7, and the dotted line shows the projecteddaily plasma concentration for oral treatment; and

FIG. 5B is a bar graph showing the number of gastrointestinal relatedadverse events (nausea, vomiting and diarrhea) reported by subjects in aclinical study, where the subjects were treated as described in FIG. 5A;the bars with dashed fill correspond to subjects treated with the weeklysmaller size transdermal patch, the bars with vertical line fillcorrespond to subjects treated with the weekly larger size transdermalpatch, and the bars with horizontal line fill correspond to the subjectstreated with oral donepezil.

DETAILED DESCRIPTION

I. Definitions

Various aspects now will be described more fully hereinafter. Suchaspects may, however, be embodied in many different forms and should notbe construed as limited to the embodiments set forth herein; rather,these embodiments are provided so that this disclosure will be thoroughand complete, and will fully convey its scope to those skilled in theart.

Where a range of values is provided, it is intended that eachintervening value between the upper and lower limit of that range andany other stated or intervening value in that stated range isencompassed within the disclosure. For example, if a range of 1 μm to 8μm is stated, it is intended that 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, and 7 μmare also explicitly disclosed, as well as the range of values greaterthan or equal to 1 μm and the range of values less than or equal to 8μm.

The singular forms “a,” “an,” and “the” include plural referents unlessthe context clearly dictates otherwise. Thus, for example, reference toa “polymer” includes a single polymer as well as two or more of the sameor different polymers, reference to an “excipient” includes a singleexcipient as well as two or more of the same or different excipients,and the like.

The word “about” when immediately preceding a numerical value means arange of plus or minus 10% of that value, e.g., “about 50” means 45 to55, “about 25,000” means 22,500 to 27,500, etc., unless the context ofthe disclosure indicates otherwise, or is inconsistent with such aninterpretation. For example in a list of numerical values such as “about49, about 50, about 55, “about 50” means a range extending to less thanhalf the interval(s) between the preceding and subsequent values, e.g.,more than 49.5 to less than 52.5. Furthermore, the phrases “less thanabout” a value or “greater than about” a value should be understood inview of the definition of the term “about” provided herein.

The terms “drug” or “active agent” or “therapeutically active agent” areused interchangeably.

An “adhesive matrix” as described herein includes matrices made in onepiece, for example, matrices made via solvent casting or extrusion aswell as matrices formed in two or more portions that are then pressed orjoined together.

“Donepezil” as used herein refers to2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one.

The terms “treatment,” “therapy,” “therapeutic” and the like, as usedherein, encompass any course of medical intervention aimed at apathologic condition, and includes not only permanent cure of a disease,but prevention of disease, control or even steps taken to mitigate adisease or disease symptoms.

The term “skin” as used herein refers to skin or mucosal tissue,including the interior surface of body cavities that have a mucosallining. The term “skin” should be interpreted as including “mucosaltissue” and vice versa.

The term “therapeutically effective amount” as used herein refers to theamount of an active agent that is nontoxic but sufficient to provide thedesired therapeutic effect. The amount that is “effective” will varyfrom subject to subject, depending on the age and general condition ofthe individual, the particular active agent or agents, and the like asknown to those skilled in the art.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, salts, compositions, dosage forms, etc., whichare—within the scope of sound medical judgment—suitable for use incontact with the tissues of human beings and/or other mammals withoutexcessive toxicity, irritation, allergic response, or other problem orcomplication, commensurate with a reasonable benefit/risk ratio. In someaspects, “pharmaceutically acceptable” means approved by a regulatoryagency of the federal or a state government, or listed in the U.S.Pharmacopeia or other generally recognized pharmacopeia for use inmammals (e.g., animals), and more particularly, in humans.

The terms “transdermal” or “transdermal delivery” as used herein referto administration of an active agent to a body surface of an individualso that the agent passes through the body surface, e.g., skin, and intothe individual's blood stream. The term “transdermal” is intended toinclude transmucosal administration, i.e., administration of a drug tothe mucosal (e.g., sublingual, buccal, vaginal, rectal) surface of anindividual so that the agent passes through the mucosal tissue and intothe individual's blood stream.

The term “treating” is used herein, for instance, in reference tomethods of treating a disorder, such as Alzheimer's disease, andgenerally includes the administration of a compound or composition whichreduces the frequency of, or delays the onset of, symptoms of a medicalcondition (e.g., Alzheimer's disease) in a subject relative to a subjectnot receiving the compound or composition. This can include reversing,reducing, or arresting the symptoms, clinical signs, and underlyingpathology of a condition in a manner to improve or stabilize a subject'scondition (e.g., regression of mental facilities).

The compositions of the present disclosure can comprise, consistessentially of, or consist of, the components disclosed.

All percentages, parts and ratios are based upon the total weight of thetopical compositions and all measurements made are at about 25° C.,unless otherwise specified.

By reserving the right to proviso out or exclude any individual membersof any such group, including any sub-ranges or combinations ofsub-ranges within the group, that can be claimed according to a range orin any similar manner, less than the full measure of this disclosure canbe claimed for any reason. Further, by reserving the right to provisoout or exclude any individual substituents, analogs, compounds, ligands,structures, or groups thereof, or any members of a claimed group, lessthan the full measure of this disclosure can be claimed for any reason.

Throughout this disclosure, various patents, patent applications andpublications are referenced. The disclosures of these patents, patentapplications and publications in their entireties are incorporated intothis disclosure by reference in order to more fully describe the stateof the art as known to those skilled therein as of the date of thisdisclosure. This disclosure will govern in the instance that there isany inconsistency between the patents, patent applications andpublications cited and this disclosure.

For convenience, certain terms employed in the specification, examplesand claims are collected here. Unless defined otherwise, all technicaland scientific terms used in this disclosure have the same meanings ascommonly understood by one of ordinary skill in the art to which thisdisclosure belongs.

II. Transdermal Delivery System and Compositions for Use in aTransdermal Delivery System

A transdermal delivery system for systemic delivery of donepezil base isprovided. The transdermal system in general is comprised of a skincontact adhesive and a drug reservoir. In one embodiment, the systemadditionally comprises an intermediate layer that is typically a fabricor membrane or other non-adhesive material, situated between the drugreservoir and the skin contact adhesive. The compositions of the layersin the system are now described.

The drug reservoir, in one embodiment, is a composition comprising asolvent mixture and donepezil base generated in situ by reaction of adonepezil salt and an alkaline salt. The drug reservoir is manufacturedusing a salt form of donepezil, e.g., donepezil hydrochloride (HCl) andan alkaline salt, that react in situ to form donepezil base. Thealkaline salt can be, for example, sodium carbonate, sodium bicarbonate,potassium carbonate, potassium bicarbonate, trisodium phosphate,disodium hydrogen phosphate, sodium oxylate, sodium succinate, sodiumcitrate, or sodium salicylate.

The solvent composition in the drug reservoir may comprise a hydrophilicsolvent in which the salt form of the active agent (e.g. donepezilhydrochloride) is soluble, a permeation enhancer, and other solvents. Inone embodiment, the hydrophilic solvent for solubilizing the salt formof the active agent is a hydrophilic solvent selected from polyethyleneglycol, propylene glycol, glycerin (glycol), acetonitrile, 1-propanol,N,N-dimethylformamide and dimethyl sulfoxide. In one embodiment, and asillustrated in the working examples herein, the hydrophilic solvent isglycerin. In some embodiments, an α-hydroxy acid as a skin penetrationenhancer is present. Enhancers in the form of α-hydroxy acid arepreferably an ester of lactic acid or glycolic acid, and an example islauryl lactate. The solvent composition, in another embodiment, alsocomprises triethyl citrate, and in other embodiments, one or both ofglycerin and sorbitan (mono)laurate are additionally present.

The drug reservoir is, in one embodiment, a polymeric adhesive layer.The adhesive layer can be formed of any of a variety of adhesivematerials, such as pressure sensitive adhesive polymers. Polyacrylatepressure sensitive adhesive polymers are an example, and typicallycomprise a polyacrylate that is a polymer or a copolymer of a monomer ormonomers selected from acrylic acid esters and methacrylic acid esters.Other monomers, such as acrylic acid and vinyl acetate, may be present.In embodiments, the acrylic polymer is based on acrylic esters such as2-ethylhexyl acrylate (2-EHA) and ethyl acrylate. In some embodiments,the polyacrylate polymer is a polymer or a copolymer of a monomer ormonomers selected from acrylic acid and vinyl acetate. In embodiments,the acrylic polymer adhesive has pendent carboxyl (—COOH) or hydroxyl(—OH) functional groups. In embodiments, the acrylic polymer adhesivecomprises at least one of polyacrylate, polymethacrylate, derivativesthereof, and co-polymers thereof. In embodiments, the acrylic adhesiveis comprised of an acrylate copolymer comprising acrylic ester monomers,acrylic acid, and/or vinyl acetate monomers. A copolymer of acrylic acidand vinyl acetate is one example. Acrylate copolymers are sold under thetrade-name Duro-TAK® and include, but are not limited to, DURO-TAK®387-2516, 387-2051, 387-2287 and 387-2074.

The drug reservoir may also comprise a copolymer such as apolyvinylpyrrolidone/vinyl acetate copolymer, an acrylic acid/vinylacetate copolymer, or a vinyl acetate/ethylene acetate copolymer. In oneembodiment, the copolymer is a vinyl acetate/N-vinylpyrrolidonecopolymer such as the copolymer sold as Plasdone™ 5630 (Ashland). Inanother embodiment, the polyvinylpyrrolidone-vinyl acetate copolymer isa linear random copolymer of n-vinyl-2-pyrrolidone and vinyl acetate. Inone embodiment, the copolymer is a 60:40 copolymer ofn-vinyl-2-pyrrolidone and vinyl acetate.

The drug reservoir may also comprise a polyvinylpyrrolidone (PVP). PVPis a water-soluble polymer comprised of the N-vinylpyrrolidone monomer,and is available in various forms, including cross-linked andnon-crosslinked. In some of the working examples herein, a cross-linkedPVP is included in the adhesive matrix drug reservoir.

In some embodiments, the drug reservoir comprises at least about 25-80wt % of adhesive polymers relative to the weight of the drug reservoir(inclusive of sub-ranges). In embodiments, the drug reservoir comprisesat least about 35-80%, at least about 30-65%, at least about 30-75%, atleast about 40-75%, at least about 50-75%, at least about 60-75%, atleast about 25-70%, at least about 30-70%, at least about 40-70%, atleast about 50-70%, at least about 60-70%, at least about 25-60%, atleast about 30-60%, at least about 40-60%, at least about 50-60%, atleast about 25-50%, at least about 30-50%, at least about 40-50%, atleast about 25-40%, at least about 30-40%, or at least about 25-30% ofan adhesive polymer or copolymer or mixture of polymers and/orcopolymers (all percentages in wt %). It will be appreciated that thedrug reservoir adhesive matrix may include one or more or at least oneadhesive polymers or copolymers. In embodiments, the adhesive matrixdrug reservoir comprises at least about 5-75% of an individual polymerrelative to the total weight of the polymers in the matrix. Inembodiments, the adhesive matrix drug reservoir comprises at least about5-10%, 5-15%, 5-20%, 5-25%, 5-30%, 5-40%, 5-50%, 5-60%, 5-70%, 5-75%,10-15%, 10-20%, 10-20%, 10-25%, 10-30%, 10-40%, 10-50%, 10-60%, 10-70%,10-75%, 15-20%, 15-25%, 15-30%, 15-40%, 15-50%, 15-60%, 15-70%, 15-75%,20-25%, 20-30%, 20-40%, 20-50%, 20-60%, 20-70%, 20-75%, 25-30%, 25-40%,25-50%, 25-60%, 25-70%, 25-75%, 30-40%, 30-50%, 30-60%, 30-70%, 30-75%,40-50%, 40-60%, 40-70%, 40-75%, 50-60%, 50-70%, 50-75%, 60-70%, 60-75%,or 70-75% of an individual polymer.

An exemplary drug reservoir comprises or consists essentially ofdonepezil base generated in situ by reaction of donepezil HCl and sodiumbicarbonate; a solvent composition comprising a hydrophilic solvent,permeation enhancer, and optionally one or both triethyl citrate andsorbitan monolaurate; a crosslinked polyvinylpyrrolidone and a copolymerof acrylic acid/vinyl acetate. In another exemplary drug reservoir, acomposition that comprises or consisting essentially of donepezil basegenerated in situ by reaction of between about 5-25 wt % or 10-25 wt %donepezil HCl and between about 1-5 wt % sodium bicarbonate; about 0-15wt % or 5-15 wt % triethyl citrate; about 0-5 wt % or 0.5-5 wt %sorbitan monolaurate; about 5-15 wt % glycerin; about 1-10 wt % lauryllactate; about 5-25 wt % crosslinked polyvinylpyrrolidone; and about30-65 wt % or 30-50 wt % acrylate-vinylacetate copolymer iscontemplated. In another example, a composition consisting essentiallyof donepezil base generated in situ by reaction of between about 10-18wt % or 14-18 wt % donepezil HCl and between about 1-5 wt % or 2-5 wt %sodium bicarbonate; about 8-12 wt % triethyl citrate; about 1.5-2.5 wt %sorbitan monolaurate; about 9-11 wt % glycerin; about 1-10 wt % lauryllactate; about 13-17 wt % crosslinked polyvinylpyrrolidone; and about40-42 wt % acrylate-vinylacetate copolymer is contemplated. Thepermeation enhancer lauryl lactate can be between about 0.5-10 wt %,0.5-7.5 wt %, 1-10 wt %, 1-7 wt %, 1-5 wt %, 2-7 wt %, 2-5 wt %, or1.5-5 wt % or 1.5-4 wt %.

A drug reservoir as described herein and hereinabove is contemplated foruse in a transdermal delivery system, where the system additionallycomprises a skin contact adhesive. The skin contact adhesive layer maybe fabricated from any of the adhesive materials listed herein andhereinabove. The skin contact adhesive layer, in one embodimentcomprises between about 50-90 wt % of adhesive polymer or copolymer, orbetween about 55-90 wt %, or between about 60-90 wt %, between about65-90 wt %, between about 70-90 wt %, between about 75-90 wt %, orbetween about 80-90 wt %. In one embodiment, the skin contact adhesiveis comprised of a copolymer of acrylic acid/vinyl acetate. In anotherembodiment, the skin contact adhesive layer additionally comprises apolyvinylpyrrolidone, such as a crosslinked polyvinylpyrrolidone.

The skin contact adhesive layer may also comprise a solvent mixture thatmay comprise a permeation enhancer. In embodiments, the skin contactadhesive layer comprises a solvent composition that comprises apermeation enhancer and one or both of triethyl citrate and sorbitanmonolaurate. In one embodiment, the skin contact adhesive layer asmanufactured does not include a pharmaceutically active agent intendedfor systemic delivery—for example, the ingredients combined to form theskin contact adhesive layer do not include donepezil base or a donepezilsalt. However, the skin contact adhesive layer when fabricated into atransdermal delivery system and stored for a period of time and/orduring use will contain the pharmaceutically active agent intended forsystemic delivery because the agent will diffuse from the drug reservoiradhesive matrix into the skin contact adhesive layer.

The penetration or permeation enhancer in either or both of the skincontact adhesive layer and the drug reservoir may be chosen from a widerange of such compounds known in the art. In some embodiments,permeation enhancers for use in the adhesive matrix include, but are notlimited to, methyl laurate, propylene glycol monolaurate, glycerolmonolaurate, glycerol monooleate, lauryl lactate, myristyl lactate, anddodecyl acetate. Additional permeation enhancers are described in U.S.Pat. No. 8,874,879, which is incorporated herein by reference. It willbe appreciated that the compositions herein may include one or more orat least one permeation enhancer. In embodiments, the penetrating orpermeating enhancer is included in an amount between about 1-10%, about2-5%, about 2-10% relative to the weight of the adhesive matrix(inclusive of sub-ranges). In other embodiments, the permeation enhanceris present in the drug reservoir and/or the contact adhesive layer in anamount between about 0.5-10 wt %, 0.5-7.5 wt %, 1-7 wt %, 1-5 wt %, 2-7wt %, 2-5 wt %, or 1.5-5 wt % or 1.5-4 wt %.

Either or both of the skin contact adhesive layer and the drug reservoirmay further include one or more matrix modifiers. Without wishing to bebound by theory, it is believed that the matrix modifier facilitateshomogenization of the adhesive matrix. Sorption of hydrophilic moietiesis a possible mechanism for this process. Thus, known matrix modifierswhich are to some degree water-sorbent may be used. For example,possible matrix modifiers include colloidal silicone dioxide, fumedsilica, cross-linked polyvinylpyrrolidone (PVP), soluble PVP, cellulosederivatives (e.g. hydroxypropyl cellulose (HPC), hydroxyethylcellulose(HEC)), polyacrylamide, polyacrylic acid, a polyacrylic acid salt, or aclay such as kaolin or bentonite. An exemplary commercial fumed silicaproduct is Cab-O-Sil (Cabot Corporation, Boston, Mass.). The hydrophilicmixtures described in U.S. Published Patent Application No. 2003/0170308may also be employed, for example mixtures of PVP and PEG or of PVP,PEG, and a water-swellable polymer such as the polymethacrylate-basedcopolymers sold under the trade name EUDRAGIT, and in particularEUDRAGIT® L100-55.

In embodiments, the matrix modifier is individually included in thecontact adhesive layer in an amount between about 1-40%, about 10-30%,about 15-25%, about 5-7%, about 7-20%, or about 7-25% relative to theweight of the adhesive matrix (inclusive of sub-ranges), including, atleast about 3%, e.g., about 4%, about 5%, about 6%, about 7%, about 8%,about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about15%, about 16%, about 17%, about 18%, about 19%, about 20%, or greater %by weight, wherein all values are relative to the weight of the entireadhesive layer. In some embodiments, the matrix modifier does notinclude ethylcellulose.

Either or both of the skin contact adhesive layer and the drug reservoirmay further include other conventional additives such as adhesiveagents, antioxidants, crosslinking or curing agents, pH regulators,pigments, dyes, refractive particles, conductive species, antimicrobialagents, opacifiers, gelling agents, viscosity modifiers or thickeningagents, stabilizing agents, and the like as known in the art. In thoseembodiments wherein adhesion needs to be reduced or eliminated,conventional detackifying agents may also be used. Other agents may alsobe added, such as antimicrobial agents, to prevent spoilage uponstorage, i.e., to inhibit growth of microbes such as yeasts and molds.Suitable antimicrobial agents are typically selected from the groupconsisting of the methyl and propyl esters of p-hydroxybenzoic acid(i.e., methyl and propyl paraben), sodium benzoate, sorbic acid,imidurea, and combinations thereof. These additives, and amountsthereof, are selected in such a way that they do not significantlyinterfere with the desired chemical and physical properties of theadhesive and/or active agent.

Either or both of the skin contact adhesive layer and the drug reservoirmay further may also contain irritation-mitigating additives to minimizeor eliminate the possibility of skin irritation and/or skin damageresulting from the drug, the enhancer, or other components of thecomposition. Suitable irritation-mitigating additives include, forexample: α-tocopherol; monoamine oxidase inhibitors, particularly phenylalcohols such as 2-phenyl-1-ethanol; glycerin; salicylic acids andsalicylates; ascorbic acids and ascorbates; ionophores such as monensin;amphiphilic amines; ammonium chloride; N-acetylcysteine; cis-urocanicacid; capsaicin; chloroquine; and corticosteriods.

A transdermal delivery system comprised of a drug reservoir and a skincontact adhesive can have a variety of configurations, and severalnon-limiting examples are depicted in are set forth in FIGS. 1A-1D. FIG.1A illustrates a transdermal delivery system 10 comprised of a drugreservoir 12 and a contact adhesive 14 separated by a rate controllingmembrane or by a non-rate controlling material, such as a tie layercomposed of a non-woven polyester or polypropylene, 16. A backing layer18 and a release liner 20 are also present. FIG. 1B illustrates a secondembodiment of a transdermal delivery system 22 comprised of a first drugreservoir 24 and a second drug reservoir 26, the first and second drugreservoirs separated by a non-rate controlling material, such as a tielayer composed of a non-woven polyester or polypropylene, 28. A contactadhesive layer 30 provides for attachment of the system to the skin of auser, where a rate controlling membrane 32 controls release oftherapeutic agent from the second drug reservoir into the contactadhesive and ultimately onto the skin of a user. A release liner 34 anda backing layer 36 are also present. FIG. 1C shows another embodiment ofa transdermal delivery system 40 comprised of a drug reservoir 42 and acontact adhesive layer 44 that provides for attachment of the system tothe skin of a user. A backing layer 46 and a release liner 48 are alsopresent.

FIG. 1D shows another embodiment of a transdermal delivery system forsystemic delivery of donepezil base. The system 50 comprises, in seriesfrom the skin facing side 52 to the external environment facing side 54,a skin contact adhesive layer 56 to attach the system to the skin of auser. In one embodiment, the skin contact adhesive layer manufactured ismanufactured from an adhesive formulation that does not comprisedonepezil base or a donepezil salt. Directly in contact with the skincontact adhesive layer is an intermediate layer 58. The intermediatelayer can be, for example, a non-woven polyester material or a drugrate-controlling membrane, such as a microporous polyethylene orpolyprolylene. The intermediate layer has opposing sides, a skin-facingside (that is in contact with the skin contact adhesive layer 56) and anenvironment facing side. On the environment facing side of theintermediate layer is a drug reservoir 60. The drug reservoir comprisesdonepezil HCl and an alkaline salt. These components react in situ togenerate donepezil base in the drug reservoir that is delivered to theuser after application of the system to the skin. In contact with thedrug reservoir layer is a first backing layer 62, and in contact withthe first backing layer is an optional adhesive overlay 64. An optionalsecond backing layer 66 is in contact with the adhesive overlay and withthe environment. In one embodiment, the optional adhesive overlay 64 iscomposed of two different adhesive layers—for example a first layer ofpolyisobutylene and polybutene, with or without a crosslinkedpolyvinylpyrrolidone, and a second layer of an acrylic adhesive. Inanother embodiment, the optional adhesive overlay 64 is composed of asingle layer of an acrylate adhesive.

Accordingly, in one embodiment a transdermal delivery system forsystemic delivery of donepezil base is provided. The system comprises,in series from the skin facing side to the external environment, a skincontact adhesive layer to attach the system to the skin of a user, theskin contact adhesive layer optionally manufactured from an adhesiveformulation that does not comprise donepezil base or a donepezil salt.Directly in contact with the skin contact adhesive layer is anintermediate layer. On the opposing surface of the intermediate layer isa drug reservoir comprised of a solvent composition and donepezil basegenerated in situ by reaction of donepezil HCl and an alkaline salt. Inone embodiment, the solvent composition comprises one or more oftriethyl citrate, a surfactant, a permeation enhancer. In a preferredembodiment, the solvent composition comprises triethyl citrate, asurfactant, an α-hydroxy acid permeation enhancer. The drug reservoir,in one embodiment, comprises an adhesive that can be a copolymer ofacrylic acid/vinyl acetate.

The intermediate layer, also referred to as a fabric layer, a membraneor a tie layer, may be formed of any suitable material including, butnot limited to, polyesters, vinyl acetate polymers and copolymers,polyethylenes, and combinations thereof. In one embodiment, theintermediate layer is a nonwoven layer of polyester fibers such as thefilm sold under the name Reemay® (Kavon Filter Products Co.). Inembodiments, the intermediate layer does not affect the rate of releaseof the active agent from the adhesive layers. In another embodiment, theintermediate layer is a rate controlling membrane for donepezil base.

In one embodiment, the intermediate layer is a microporous membranecomprising a plurality of pores. In exemplary transdermal systemsprepared as described in the working examples, the plurality of pores inthe microporous membrane contains a solvent composition. In oneembodiment, the solvent composition in the pores of the microporousmembrane is comprised of one or more of the solvents present in eitheror both of the drug reservoir and the contact adhesive. For example, anexemplary solvent composition contained in the pores of the microporousmembrane is one or more of triethyl citrate, a surfactant, an α-hydroxyacid permeation enhancer. Another exemplary embodiment is a solventcomposition comprised of one or more of triethyl citrate, sorbitanmonolaurate, and lauryl lactate. In one embodiment, the solventcomposition comprises between 40-80 wt % triethyl citrate, between 5-40wt % lauryl lactate and between 5-25 wt % sorbitan laurate. In anotherembodiment, the solvent composition comprises between 50-75 wt % or55-70 wt % triethyl citrate, between 10-35 wt % or 15-30 wt % lauryllactate and between 8-20 wt % or between 10-15 wt % sorbitan laurate. Inone embodiment, the solvent composition contained in the pores of themicroporous membrane excludes the hydrophilic solvent present in thedrug reservoir. In one embodiment, the solvent composition contained inthe pores of the microporous membrane excludes glycerin.

The microporous membrane may be pretreated with the solvent compositionso that its pores are saturated with, filled with, or partially filledwith the solvent composition. The microporous membrane is, in oneembodiment, a polypropylene microporous membrane and may have an averagepore size in the range of about 0.001 μm to about 100 μm, about 1μm toabout 10 μm, about 0.010 μm to about 0.100 μm, or about 0.040 μm toabout 0.050 μm. For example, the average pore size can be about 0.035μm, 0.036 μm, 0.037 μm, 0.038 μm, 0.039 μm, 0.040 μm, 0.041 μm, 0.042μm, 0.043 μm, 0.044 μm, 0.045 μm, 0.046 μm, 0.047 μm, 0.048 μm, 0.049μm, or 0.050 μm. In some embodiments, the microporous membrane has anaverage pore size of about 0.043 μm. The microporous membrane is, in oneembodiment, a polypropylene microporous membrane and has a porosity inthe range of about 30% to about 50%, about 35% to about 45%, or about40% to about 42%. For example, the microporous membrane can have aporosity of about 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%,41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, or 50%.

The adhesive overlay in the delivery system of FIG. 1D is comprised, inone embodiment, of a polyisobutylene and polybutene mixture. In anotherembodiment, the adhesive overlayer is comprised of a first layer and asecond layer, the first layer composed of a polyisobutylene, polybuteneand crosslinked polyvinylpyrrolidone mixture and the second layercomposed of an acrylic adhesive. Polyisobutylene is a vinyl polymercomprised of the isobutylene monomer. Polybutene is a viscous,non-drying, liquid polymer, prepared by copolymerization of 1- and2-butene with a small quantity of isobutylene. In some embodiments, thepolybutene in one embodiment has a molecular weight of between about750-6000 Daltons, preferably between about 900-4000 Daltons, andpreferably between about 900-3000 Daltons. In some embodiments themixture comprises polybutene in the polyisobutylene blend at about 40weight percent. More generally, the polybutene is present in thepolyisobutylene blend in an amount between 20-50 weight percent, orbetween 25-45 weight percent. In another embodiment, the adhesiveoverlayer is a single layer and comprised of an acrylate copolymer thatforms the single layer adhesive overlay. An exemplary acrylate copolymeris DuroTak® 387-2052.

The transdermal delivery system comprises a backing layer that providesa structural element for holding or supporting the underlying adhesivelayer(s). The backing layer may be formed of any suitable material asknown in the art. In some embodiments, the backing layer is occlusive.In some embodiments, the backing is preferably impermeable orsubstantially impermeable to moisture. In one exemplary embodiment, thebarrier layer has a moisture vapor transmission rate of less than about50 g/m²-day. In some embodiments, the backing layer is preferably inertand/or does not absorb components of the adhesive layer, including theactive agent. In some embodiments, the backing layer preferably preventsrelease of components of the adhesive layer through the backing layer.The backing layer may be flexible or nonflexible. The backing layer ispreferably at least partially flexible such that the backing layer isable to conform at least partially to the shape of the skin where thepatch is applied. In some embodiments, the backing layer is flexiblesuch that the backing layer conforms to the shape of the skin where thepatch is applied. In some embodiments, the backing layer is sufficientlyflexible to maintain contact at the application site with movement, e.g.skin movement. Typically, the material used for the backing layer shouldpermit the device to follow the contours of the skin or otherapplication site and be worn comfortably on areas of skin such as atjoints or other points of flexure, that are normally subjected tomechanical strain with little or no likelihood of the device disengagingfrom the skin due to differences in the flexibility or resiliency of theskin and the device.

In some embodiments, the backing layer is formed of one or more of afilm, non-woven fabric, woven fabric, laminate, and combinations thereofIn some embodiments, the film is a polymer film comprised of one or morepolymers. Suitable polymers are known in the art and include elastomers,polyesters, polyethylene, polypropylene, polyurethanes and polyetheramides. In some embodiments, the backing layer is formed of one or moreof polyethylene terephthalate, various nylons, polypropylene, metalizedpolyester films, polyvinylidene chloride, and aluminum foil. In someembodiments, the backing layer is a fabric formed of one or more ofpolyesters such as polyethylene terephthalate, polyurethane, polyvinylacetate, polyvinylidene chloride and polyethylene. In one particular,but non-limiting embodiment, the backing layer is formed of a polyesterfilm laminate. One particular polyester film laminate is thepolyethylene and polyester laminate such as the laminate sold under thename SCOTCHPAK™ #9723.

In embodiments, the device includes a release liner at least partiallyin contact at least with the adhesive layer to protect the adhesivelayer prior to application. The release liner is typically a disposablelayer that is removed prior to application of the device to thetreatment site. In some embodiments, the release liner preferably doesnot absorb components of the adhesive layer, including the active agent.In some embodiments, the release liner preferably impermeable tocomponents of the adhesive layer (including the active agent) andprevents release of components of the adhesive layer through the releaseliner. In some embodiments, the release liner is formed of one or moreof a film, non-woven fabric, woven fabric, laminate, and combinationsthereof. In some embodiments, the release liner is a silicone-coatedpolymer film or paper. In some non-limiting embodiments, the releaseliner is a silicone-coated polyethylene terephthalate (PET) film, afluorocarbon film, or a fluorocarbon coated PET film.

The thickness and/or size of the device and/or adhesive matrices may bedetermined by one skilled in the art based at least on considerations ofwearability and/or required dose. It will be appreciated that theadministration site for the device will affect the wearabilityconsiderations due to the available size of the administration site andthe use of the administration site (e.g. need for flexibility to supportmovement). In some embodiments, the device and/or adhesive matrix has athickness of between about 25-500 μm. In some embodiments, the deviceand/or adhesive matrix has a thickness of between about 50-500 μm. Insome embodiments, the patch has a size in the range of about 16 cm²-225cm². It will be appreciated that the thickness and size provided hereare merely exemplary and the actual thickness and or size may bethinner/smaller or thicker/larger as needed for a specific formulation.

Fabrication of a transdermal delivery system is routinely done byskilled artisans and involves casting or extruding each of the adhesivelayers onto a suitable film such as a release liner or onto anotherlayer of the transdermal delivery system, and drying if needed to removesolvents and/or volatile compounds. Layers of the transdermal deliverysystem can be laminated together to form the final system.

Transdermal delivery systems and drug reservoir adhesive matrices wereprepared to illustrate the embodiments described herein. Examples 1-3set forth exemplary compositions and delivery systems. As described inExample 1, a transdermal delivery system comprised a drug reservoir anda contact adhesive with a rate controlling membrane situated between thedrug reservoir and the contact adhesive, as depicted in FIG. 1A. A drugreservoir in the form of a solid monolithic adhesive reservoir wasprepared using an acrylic acid/vinyl acetate copolymer adhesive with asolvent mixture that included a permeation enhancer. In one embodiment,the solvent mixture is comprised of triethyl citrate, lauryl lactate andsorbitan monolaurate. The drug reservoir contained approximately 5 wt %donepezil hydrochloride and sodium bicarbonate, to generate in situdonepezil base. A contact adhesive layer comprised of the same acrylicacid/vinyl acetate copolymer adhesive, along with triethyl citrate,lauryl lactate and ethyl acetate was prepared. A rate controllingmembrane, to control the diffusional release of donepezil base from thedrug reservoir, separated the drug reservoir and the contact adhesive.

As described in Examples 2 and 3, transdermal delivery systems wereprepared and were comprised of an adhesive matrix drug reservoir and askin contact adhesive layer separated by an intermediate layer. Theadhesive matrix drug reservoir in the exemplary systems comprised theadhesive copolymer acrylic acid/vinyl acetate and in one exampleadditionally included a cross-linked polyvinylpyrrolidone (Example 2).The acrylic acid/vinyl acetate was added to a solvent mixture thatcomprised a permeation enhancer (the solvent mixture in this embodimentwas triethyl citrate, sorbitan monolaurate, lauryl lactate, andglycerin), donepezil hydrochloride and sodium bicarbonate. The skincontact adhesive layer was comprised of sorbitan monolaurate, triethylcitrate, and lauryl lactate, along with acrylic acid/vinyl acetatecopolymer. In these exemplary delivery systems, a microporous membraneto control the rate of release of donepezil base from the adhesivematrix drug reservoir was laminated to one side of the rate controllingmembrane was situated between the adhesive matrix drug reservoir and theskin contact adhesive. A release liner and a backing member werelaminated to form a final delivery system.

Accordingly, in one embodiment, a composition comprising an adhesivematrix comprising or consisting essentially of donepezil base generatedin situ by reaction of donepezil HCl and sodium bicarbonate; a solventcomposition comprised of triethyl citrate, sorbitan monolaurate, andglycerin; and a polymeric, adhesive matrix of crosslinkedpolyvinylpyrrolidone and a copolymer of acrylic acid/vinyl acetate isprovided. In another embodiment, a composition, comprising an adhesivematrix comprising or consisting essentially of donepezil base generatedin situ by reaction of between about 10-25 wt % donepezil HCl andbetween about 1-5 wt % sodium bicarbonate; about 5-15 wt % triethylcitrate; about 0.5-5 wt % sorbitan monolaurate; about 5-15 wt %glycerin; about 5-25 wt % crosslinked polyvinylpyrrolidone; and about30-50 wt % acrylate-vinylacetate copolymer is provided. In anotherembodiment, composition comprising an adhesive matrix comprising orconsisting essentially of donepezil base generated in situ by reactionof between about 14-18 wt % donepezil HCl and between about 2-5 wt %sodium bicarbonate; about 8-12 wt % triethyl citrate; about 1.5-2.5 wt %sorbitan monolaurate; about 9-11 wt % glycerin; about 13-17 wt %crosslinked polyvinylpyrrolidone; and about 40-42 wt %acrylate-vinylacetate copolymer is provided.

The compositions described are intended for use in a transdermaldelivery system for systemic delivery of donepezil. The adhesivecompositions are manufactured using a salt form of donepezil and a weakbase (alkaline salt), to generate in situ the base form of donepezilthat is delivered via the skin for systemic uptake. The transdermaldelivery system also comprises one or more of triethyl citrate, lauryllactate, glycerin, sorbitan laurate, and ethyl acetate in the drugreservoir, and one or more of triethyl citrate, lauryl lactate, sorbitanlaurate, and ethyl acetate in the skin contact adhesive. In oneembodiment, the drug reservoir and the contact adhesive each compriseone or more of triethyl citrate, lauryl lactate and sorbitan laurate. Inone embodiment, the skin contact adhesive does not comprise glycerin. Inanother embodiment, the transdermal system comprises a microporousmembrane with a plurality of pores that contain, are filled or partiallyfilled, or saturated with one or more of the same solvents in one orboth of the drug reservoir and the contact adhesive. In one embodiment,the plurality of pores in the microporous membrane comprise a solventcomposition that comprises one or more of triethyl citrate, lauryllactate and sorbitan laurate. The triethyl citrate may be present in thedrug reservoir, the pores of the microporous membrane, and/or thecontact adhesive in an amount between about 1-20 wt %, 2-25 wt %, 5-15wt %, 5-12 wt %, 7-15 wt %, 7-12 wt %, 8-12 wt %, 9-12 wt %, 1-8 wt %,1-6 wt %, 1-5 wt %, 1.5-5 wt %, 2-5 wt % or 2.5-5 wt % or 2.5-4.5 wt %.Ethyl acetate may be present in the drug reservoir, the pores of themicroporous membrane, and/or the contact adhesive in an amount betweenabout 25-60 wt %, where in one embodiment, a greater amount of ethylacetate is present in the drug reservoir than in the contact adhesive,where the drug reservoir comprises 1.2, 1.3, 1.4, 1.5, 1.6, 1.7 or 1.8times more ethyl acetate than the contact adhesive layer. Sorbitanlaurate may be present in the drug reservoir, the pores of themicroporous membrane, and/or the contact adhesive in an amount betweenabout 0.01-5 wt % or 0.1-5 wt %, where in one embodiment, sorbitanlaurate is present in the drug reservoir and in the contact adhesive inthe same amounts (on a w/w basis of the total amount in each layerindividually, e.g., the amount in weight percent in the drug reservoirlayer is the same as the amount in weight percent in the contactadhesive layer). In another embodiment, the drug reservoir, the pores ofthe microporous membrane, and/or the contact adhesive comprise lauryllactate in an amount between about 0.1-10 wt %, 0.5-8 wt % or 0.5-7 wt%, 1-7 wt %, 1-5 wt %, 1.5-5 wt %, 2-5 wt %, 2.5-5 wt %, 0.25-5 wt %,0.5-5 wt % or 0.5-4 wt %, 0.5-4.5 wt %. In one embodiment, the drugreservoir comprises an amount of lauryl lactate that is equal to orwithin about 0.5%, 1%, 5 wt %, 10 wt %, 15wt % or 20 wt % of the amountof lauryl lactate present in the contact adhesive layer.

III. Method of Treatment

Based on the exemplary compositions and transdermal delivery systems(also referred to as transdermal devices or devices) described herein, amethod for treating a suitable condition with donepezil is provided. Inembodiments, compositions and devices comprising donepezil are usefulfor treating, delaying progression, delaying onset, slowing progression,preventing, providing remission, and improvement in symptoms ofcognitive disorders or disease are provided herein. In embodiments,compositions and devices comprising donepezil are provided formaintaining mental function including, but not limited to a least one ofmaintaining thinking, memory, speaking skills as well as managing ormoderating one or more behavioral symptoms of a cognitive disorder ordisease. In embodiments, the cognitive disorder is Alzheimer's disease.In particular embodiments, the cognitive disorder is Alzheimer's typedementia. In embodiments, compositions and devices comprising donepezilare provided for use in treating, etc. mild, moderate, or severeAlzheimer's disease.

Alzheimer's disease is the most common cause of senile dementia and ischaracterized by cognitive deficits related to degeneration ofcholinergic neurons. Alzheimer's affects 6-8% of people over the age of65 and nearly 30% of people over the age of 85 (Sozio et al.,Neurophsychiatric Disease and Treatment, 2012, 8:361-368), involving theloss of cognitive functioning and behavioral abilities. The causes ofAlzheimer's disease are not yet fully understood. As Alzheimer's diseaseis associated with reduced levels of several cerebral neurotransmittersincluding acetylcholine (Ach), current treatment includes administeringcholinesterase inhibitors. Cholinesterase inhibitors reduce thehydrolysis of acetylcholine in the synaptic cleft by inhibitingcholinesterase and/or butyrylcholinesterase, which increasesacetylcholine levels resulting in improved neurotransmission (Id.).

The transdermal devices described herein may be designed for long termuse and/or continuous administration of the active agent. The FDA hasapproved daily oral doses of donepezil of 5 mg, 10 mg, and 23 mg. Itwill be appreciated that the total dose of the active agent pertransdermal device will be determined by the size of the device and theloading of the active agent within the adhesive matrix. In anembodiment, the active agent is donepezil in free base form. Lower drugloading of donepezil base may be effective as compared to the salt form(e.g. donepezil hydrochloride). The ability to include lower drugloading to achieve efficacy results in a lower profile for the device(thinner) and/or smaller size, both of which are desirable to reducediscomfort. In some embodiments, the application period for thetransdermal device is between about 1-10 days, 1-7 days, 1-5 days, 1-2days, 3-10 days, 3-7 days, 3-5 days, 5-10 days, and 5-7 days inclusive.In some embodiments, the active agent is released from the adhesivematrix as a continuous and/or sustained release over the applicationperiod.

A method for delivering donepezil base transdermally to a subject isprovided. In the method a transdermal delivery system is applied to theskin, and upon application of the transdermal delivery system to theskin of a subject, transdermal delivery of the donepezil base occurs, toprovide a systemic blood concentration of the agent (or a metabolite)that at steady state is bioequivalent to administration of thetherapeutic agent orally. As discussed below, bioequivalency isestablished by (a) a 90% confidence interval of the relative mean Cmaxand AUC of the therapeutic agent administered from the transdermaldelivery system and via oral delivery between 0.7-1.43 or between 0.80and 1.25, or (b) a 90% confidence interval of the ratios for AUC andCmax of the therapeutic agent administered from the transdermal deliverysystem and via oral delivery between 0.7-1.43 or between 0.80 and 1.25

Standard PK parameters routinely used to assess the behavior of a dosageform in vivo (in other words when administered to an animal or humansubject) include C_(max) (peak concentration of drug in blood plasma),T_(max) (the time at which peak drug concentration is achieved) and AUC(the area under the plasma concentration vs time curve). Methods fordetermining and assessing these parameters are well known in the art.The desirable pharmacokinetic profile of the transdermal deliverysystems described herein comprise but are not limited to: (1) a C_(max)for transdermally delivered form of the donepezil when assayed in theplasma of a mammalian subject following administration, that isbioequivalent to the C_(max) or an orally delivered or an intraveneouslydelivered form of the drug, administered at the same dosage; and/or (2)an AUC for transdermally delivered form of donepezil when assayed in theplasma of a mammalian subject following administration, that ispreferably bioequivalent to the AUC for an orally delivered or anintraveneously delivered form of the drug, administered at the samedosage; and/or (3) a T_(max) for transdermally delivered form ofdonepezil when assayed in the plasma of a mammalian subject followingadministration, that is within about 80-125% of the T_(max) for anorally delivered or an intraveneously delivered form of the drug,administered at the same dosage. Preferably the transdermal deliverysystem exhibits a PK profile having a combination of two or more of thefeatures (1), (2) and (3) in the preceding sentence. Preferably thetransdermal delivery system exhibits a PK profile having one or both ofthe features (1) and (2).

In the field of pharmaceutical development the term “bioequivalence”will be readily understood and appreciated by the person skilled in theart. Various regulatory authorities have strict criteria and tests forassessing whether or not two drug products are bioequivalent. Thesecriteria and tests are commonly used throughout the pharmaceuticalindustry and the assessment of bioequivalence is recognized as astandard form of activity in drug development programs where thecharacteristics and performance of one product are being compared tothose of another product. Indeed in seeking approval to market certaintypes of products (e.g. those evaluated under the FDA's “Abbreviated NewDrug Application” procedure), it is a requirement that the follow-onproduct be shown to be bioequivalent to a reference product.

In one embodiment, the method encompasses providing and/or administeringa transdermal delivery system comprising donepezil base to a subject ina fasted state is bioequivalent to administration of the agent (in baseor salt form) orally or intravenously to a subject also in a fastedstate, in particular as defined by C_(max) and AUC guidelines given bythe U.S. Food and Drug Administration and the corresponding Europeanregulatory agency (EMEA). In another embodiment, the method encompassesproviding and/or administering a transdermal delivery system comprisingdonepezil base to a subject in a fasted state is bioequivalent toadministration of the agent (in base or salt form) orally orintravenously to a subject also in a non-fasted or fed state. Under U.S.FDA and Europe's EMEA guidelines, two products or methods arebioequivalent if the 90% Confidence Intervals (CI) for AUC and C_(max)are between 0.80 to 1.25 (T_(max) measurements are not relevant tobioequivalence for regulatory purposes). Europe's EMEA previously used adifferent standard, which required a 90% CI for AUC between 0.80 to 1.25and a 90% CI for C_(max) between 0.70 to 1.43. Methods for determiningC_(max) and AUC are well known in the art.

The transdermal delivery system prepared according to Example 1 wastested in vivo for systemic delivery of donepezil, as described inExample 4. In this in vivo study, six human subjects received treatmentwith a transdermal delivery system applied to their skin and worn forone week, and then removed. Another group of six human subjects weretreated with orally administered donepezil (ARICPET®) at a dose of 5 mgtaken on day one and on day 7 of the study. Blood samples were takenfrom the subjects and plasma concentrations of donepezil determined. Theresults are shown in FIGS. 2A-2B.

FIG. 2A shows the mean plasma concentration of donepezil, in ng/mL, inhuman subjects treated with a donepezil transdermal delivery system(circles) for 1 week, or with 5 mg of donepezil administered orally onday 1 and on day 7 (triangles). The donepezil transdermal deliverysystem provided a plasma concentration similar to the plasmaconcentration provided from oral delivery of a similar dose ofdonepezil. Accordingly, in one embodiment, a method of administeringdonepezil transdermally is provided by administering a transdermaldelivery system that provides a pharmacokinetic profile that isbioequivalent to the pharmacokinetic profile obtained by oraladministration of donepezil.

FIG. 2B is a graph showing a close up of the data points from FIG. 2A inthe 24 hour period after oral administration of the 5 mg donepeziltablet (triangles) and after removal of the donepezil transdermaldelivery system (circles). The transdermal delivery system provides asustained, constant donepezil plasma concentration for 24 hours afterits removal, similar to that observed in the 24 hour post oraladministration.

FIG. 3 is a graph showing the projected mean plasma concentration ofdonepezil, in ng/mL, in the last week of a 28 day (4 week) treatmentperiod with a transdermal delivery system designed to administer 10mg/day for a week (solid line) and over a 28 day period with a 10 mgdaily oral tablet of donepezil (dashed line). The plasma fluctuationsresulting from oral administration are eliminated by the transdermalsystem, where a fresh patch is applied each week and a constant plasmaconcentration is maintained over the treatment period. The transdermaldelivery system provides a constant plasma concentration of donepezilfor a sustained period of time (e.g., 3 days, 5 days, 7 days, 14 days),where the plasma concentration is essentially the same as or withinabout 10%, 15%, 20% or 30% of the plasma concentration achieved withdaily oral administration of a similar daily dose of donepezil.

With reference again to the study in Example 4, the six subjects treatedwith a donepezil transdermal delivery system for one week were monitoredfor several days following removal of the delivery system from theirskin for signs of skin irritation. FIG. 4 is a bar graph showing thenumber of subjects out of the 6 in the group and the observed skinirritation in the period after removal of the delivery system, where theopen bars indicate no skin irritation and the filled bars indicate mildskin irritation. The delivery system resulted in no or mild skinirritation in the hours after removal, and any mild irritation resolvedwith a day or two.

In another study, human subjects were treated with a transdermaldelivery system designed to deliver systemically an amount of donepezilthat is bioequivalent to orally administered donepezil at a 10 mg, oncedaily dose. The projected pharmacokinetic parameters Cmax, AUC and Cminfor the two routes of delivery are compared in Table 1.

TABLE 1 Projected Pharmacokinetic Parameters Once-weekly transdermal 10mg oral Geometric Mean PK Parameter at delivery donepezil, once RatioSteady State system daily (transdermal:oral) Geometric mean C_(max) 40.645.6 0.890 (ng/ml) Geometric mean C_(min) 34.2 30.8 1.110 (ng/ml)Geometric mean 6367 6165*   1.033 AUC_(week) (ng-hr/ml)

Accordingly, in one embodiment, a method for delivering donepezil baseto a subject is provided. The method comprises providing a transdermaldelivery system comprised of donepezil, and administering or instructingto administer the transdermal delivery system to the skin of a subject.The method achieves transdermal delivery of donepezil that isbioequivalent to administration of the therapeutic agent orally, whereinbioequivalency is established by (a) a 90% confidence interval of therelative mean Cmax and AUC of the therapeutic agent administered fromthe transdermal delivery system and via oral delivery between 0.70-1.43or between 0.80 and 1.25, or (b) a 90% confidence interval of thegeometric mean ratios for AUC and Cmax of the therapeutic agentadministered from the transdermal delivery system and via oral deliverybetween 0.70-1.43 or between 0.80 and 1.25.

Example 5 describes a study conducted on human subjects wheretransdermal patches comprising donepezil were studied and compared toorally administered donepezil. In this study, patients were enrolled toparticipate in a six month, three-period, randomized crossover studycomparing the steady-state pharmacokinetic profiles of once-daily oraldonepezil (ARICEPT®) with a donepezil transdermal patch formulation. Thetransdermal patch was provided in two sizes, A and B, yet other thansurface area, the transdermal patches were the same in all respects.During the study, the participants in each treatment arm received oneweek of 5 mg/day of donepezil, followed by 4 weeks of 10 mg/day ofdonepezil delivered from a once-weekly transdermal patch of two sizes(Arm 1 and Arm 2) or orally (Arm 3). Pharmacokinetic measurements wereevaluated during the fourth week of the 10 mg/day treatment, when plasmaconcentrations had achieved steady levels. Blood samples for thesubjects receiving the transdermal treatment were taken daily throughoutthe fourth week to determine pharmacokinetics. Subjects receiving oraldonepezil had blood drawn on the last day of the fourth week todetermine pharmacokinetics. The mean plasma concentration of donepezil,in ng/mL, is shown in FIG. 5A, for each day in week 5 of the study,where the solid line corresponds to the transdermal patch with a smallersurface area and the dashed line corresponds to the transdermal patchwith a larger surface area. The thick, bold line at days 6-7 shows themean plasma concentration for the subjects receiving the oral donepezil,and the dotted line shows the projected daily plasma concentration fororal treatment. The mean plasma concentrations of donepezil in thesubjects treated with a transdermal patch were bioequivalent to theplasma concentration of donepezil in the subject treated orally withdonepezil. The larger and smaller transdermal patches demonstrated doseproportionality. Table 2 shows the primary pharmacokinetic parameters ina bioequivalence assessment of the smaller surface area transdermalpatch used in the study.

TABLE 2 Primary Pharmacokinetic Geometric Mean Ratio (%) ofBioequivalence Limits Parameter smaller patch to oral dose (target80-125%) AUC (ng-hr/mL) 104.7% 95.2-115.2 Cmax_(ss) (ng/mL) 91.6%83.1-100.8

The gastrointestinal related adverse events of nausea, vomiting anddiarrhea reported by the subjects in the clinical study mentioned abovewith respect to FIG. 5A are shown in FIG. 5B. Subjects treated with thesmaller size transdermal patch (bars with dashed fill) and with thelarger size transdermal patch (bars with vertical line fill) had a lowerincidence or nausea, vomiting and diarrhea than subjects treated withoral (bars with horizontal line fill) donepezil. The number of subjectsexperiencing nausea was four-fold lower when the 10 mg/day donepezil wasadministered transdermally versus orally. The number of subjectsexperiencing diarrhea was two-fold lower when 10 mg/day donepezil wasadministered transdermally versus orally.

Accordingly, in one embodiment, a composition and a method fordelivering donepezil to a subject is provided. The composition, whenapplied to the skin of a subject, provides transdermal delivery ofdonepezil to achieve a plasma concentration of donepezil that at steadystate is bioequivalent to administration of donepezil orally, and/orthat provides a number of gastrointestinal related adverse events thatis two-fold, three-fold, four-fold, or five-fold lower than subjectstreated with the same dose of donepezil orally (i.e., the dose givenorally is equal to the dose given transdermally, such that the subjectsare treated with an equal dose of donepezil given orally ortransdermally). In one embodiment, the donepezil given orally is a saltform of donepezil and the donepezil given transdermally is donepezilbase. In one embodiment, the number of gastrointestinal related adverseevents is between 2-5, 2-4, and 2-3 fold lover, and in anotherembodiment, the number of gastrointestinal related adverse events is atleast about two-fold, at least about three-fold, at least aboutfour-fold, or at least about five-fold lower than subjects treated withthe same dose of donepezil orally. In one embodiment, the delivery ofdonepezil is for the treatment of Alzheimer's disease.

IV. Examples

The following examples are illustrative in nature and are in no wayintended to be limiting.

Example 1 Donepezil Transdermal Delivery System

A transdermal delivery system comprising donepezil was prepared asfollows.

Preparation of drug reservoir: 1.20 grams of sorbitan monolaurate (SPAN®20) was dissolved in 6.00 g of triethyl citrate and mixed with 1.80grams of lauryl lactate and 89.69 grams of ethyl acetate. 6.00 grams ofglycerin was added and mixed. 9.00 grams of donepezil hydrochloride and1.82 grams of sodium bicarbonate were added and dispersed in themixture. 12.00 grams of crosslinked, micronized polyvinylpyrrolidone(Kollidon® CL-M) was then added and the mixture was homogenized. To thehomogenized drug dispersion, 43.93 grams of acrylic acid/vinyl acetatecopolymer (Duro-Tak 387-2287, solid content 50.5%) was added and wellmixed. The wet adhesive formulation was coated on a release liner anddried using a lab coater (Werner Mathis) to yield a dry coat weight of12 mg/cm².

Preparation of contact adhesive: 0.60 grams of sorbitan monolaurate(SPAN® 20) was dissolved in 3.0 grams of triethyl citrate and mixed with0.9 grams of lauryl lactate, 25.45 grams of ethyl acetate and 1.34 gramsof isopropyl alcohol. 6.00 grams of crosslinked, micronizedpolyvinylpyrrolidone (Kollidon® CL-M) was added and the mixture washomogenized. To the homogenized mixture 38.61 grams of acrylicacid/vinyl acetate copolymer (Duro-Tak® 387-2287, solid content 50.5%)was added and mixed well. The wet adhesive formulation was coated on arelease liner and dried to give a dry coat weight of 5 mg/cm².

Lamination and die-cut: A rate controlling membrane (CELGARD® 2400 orReemay 2250) was laminated on the adhesive side of the drug reservoir.Then the contact adhesive was laminated on top of the rate controllingmembrane laminated with drug reservoir. The release liner on the drugreservoir side was replaced and laminated with backing film. The finalfive layer laminate was die-cut into transdermal patches.

The weight percentage of the components in the transdermal deliverysystem are set forth in Table 1.1 below.

TABLE 1.1 wt. % in drug wt. % in contact total wt. % in Ingredientreservoir adhesive delivery system Donepezil HCl 5.2% — 3.6% Sodiumbicarbonate 1.1% — 0.74%  sorbitan monolaurate 0.7% 0.8% 0.73%  (Span ®20) Triethyl citrate 3.5% 3.9% 3.6% Lauryl lactate 1.05%  1.2% 1.1%Ethyl acetate 52.3%  33.5%  46.6%  Glycerin 3.5% — 2.4% crosslinked,micronized 7.0% 7.9% 7.3% polyvinylpyrrolidone (Kollidon ® CL-M) acrylicacid/vinyl 25.6%  50.9%  33.4%  acetate copolymer (Duro-Tak ® 387-2287)isopropyl alcohol — 1.8% 0.54% 

Example 2 Donepezil Transdermal Delivery Systems

Transdermal delivery system comprising donepezil was prepared asfollows.

Preparation of drug reservoir: Sorbitan monolaurate (SPAN® 20) wasdissolved in triethyl citrate and mixed with lauryl lactate. Glycerinwas added and mixed. Donepezil hydrochloride and sodium bicarbonate wereadded and dispersed in the mixture. Crosslinked, micronizedpolyvinylpyrrolidone (KOLLIDON® CL-M) was then added and the mixture washomogenized. To the homogenized drug dispersion, acrylic acid/vinylacetate copolymer (DURO-TAK® 387-2287, solid content 50.5%) was addedand well mixed. The wet adhesive formulation was coated on a releaseliner and dried using a lab coater (Werner Mathis).

Preparation of contact adhesive: Sorbitan monolaurate (SPAN® 20) wasdissolved in triethyl citrate and mixed with lauryl lactate.Crosslinked, micronized polyvinylpyrrolidone (Kollidon® CL-M) was addedand the mixture was homogenized. To the homogenized mixture acrylicacid/vinyl acetate copolymer (DURO-TAK ° 387-2287, solid content 50.5%)was added and mixed well. The wet adhesive formulation was coated on arelease liner and dried.

Lamination and die-cut: A polypropylene microporous membrane (Celgard®2400) was pretreated by coating it with a solvent mixture of sorbitanmonolaurate, triethyl citrate and lauryl lactate to saturate themembrane with the solvent mixture. The pretreated membrane was laminatedon the adhesive side of the drug reservoir. Then the contact adhesivewas laminated on top of the rate controlling membrane laminated withdrug reservoir. The release liner on the drug reservoir side wasreplaced and laminated with backing film. The final five layer laminatewas die-cut into transdermal patches.

The weight percentage of the components in the transdermal deliverysystems are set forth in Table 2.1 below.

TABLE 2.1 Contact Adhesive Drug Reservoir (Dry formula, % Ingredient(Dry Formula % wt/wt) wt/wt) Donepezil HCl 16.0 0 Sodium bicarbonate 2.60 Triethyl citrate 10.0 10.0 Lauryl Lactate 3.0 3.0 Sorbitan monolaurate2.0 2.0 (SPAN ® 20) Glyerine 10.0 0 PVP-CLM 15.0 20.0 (KOLLIDONE ®-CLM)acrylic acid/vinyl acetate 41.4 65.0 copolymer (Duro-Tak ® 387-2287)

Example 3 Donepezil Transdermal Delivery Systems

Transdermal delivery system comprising donepezil was prepared asfollows.

Preparation of drug reservoir: Sorbitan monolaurate (SPAN® 20) wasdissolved in triethyl citrate and mixed with lauryl lactate. Glycerinwas added and mixed. Donepezil hydrochloride was added and dispersed inthe mixture. Fumed silica (AEROSIL° 200 Pharma) was then added and themixture was homogenized. To the homogenized drug dispersion, acrylicacid/vinyl acetate copolymer (DURO-TAK ° 387-2287, solid content 50.5%)and dime thylaminoethyl methacrylate, butyl methacrylate, methylmethacrylate copolymer (EUDRAGIT® EPO) were added and well mixed. Thewet adhesive formulation was coated on a release liner and dried using alab coater (Werner Mathis).

Preparation of contact adhesive: Sorbitan monolaurate (SPAN® 20) wasdissolved in triethyl citrate and mixed with lauryl lactate.Crosslinked, micronized polyvinylpyrrolidone (KOLLIDON® CL-M) was addedand the mixture was homogenized. To the homogenized mixture acrylicacid/vinyl acetate copolymer (Duro-Tak® 387-2287, solid content 50.5%)added and mixed well. The wet adhesive formulation was coated on arelease liner and dried.

Lamination and die-cut: A polypropylene microporous membrane (Celgard®2400) was pretreated by coating it with a solvent mixture of sorbitanmonolaurate, triethyl citrate and lauryl lactate to saturate themembrane with the solvent mixture. The pretreated membrane was laminatedon the adhesive side of the drug reservoir. Then the contact adhesivewas laminated on top of the rate controlling membrane laminated withdrug reservoir. The release liner on the drug reservoir side wasreplaced and laminated with backing film. The final five layer laminatewas die-cut into transdermal patches.

The weight percentage of the components in the transdermal deliverysystems are set forth in Table 3.1 below.

TABLE 3.1 Contact Drug Reservoir Adhesive (Dry Formula % (Dry formula, %Ingredient wt/wt) wt/wt) Donepezil HCl 25.0 0 dimethylaminoethylmethacrylate, 17.7 0 butyl methacrylate, methyl methacrylate copolymer(EUDRAGIT ® EPO) Triethyl citrate 10.0 10.0 Lauryl Lactate 6.0 6.0Sorbitan monolaurate 2.0 2.0 (SPAN ® 20) fumed silica 7.0 0 (AEROSIL ®200 Pharma) Glyerine 10.0 0 PVP-CLM 0 20.0 (KOLLIDONE ®-CLM) acrylicacid/vinyl acetate 24.3 64.0 copolymer (Duro-Tak ® 387-2287)

Example 4 In Vivo Administration of Donepezil from a DonepezilTransdermal Delivery System

Transdermal delivery systems comprising donepezil were prepared asdescribed in Example 1. Twelve (12) human subjects were randomized intotwo groups for treatment with a transdermal delivery system (n=6) orwith orally administered donepezil (ARICPET®), 5 mg taken on day one andon day 7 of the study. The transdermal delivery system was applied tothe skin and worn for one week and then removed. Blood samples weretaken daily from the subjects treated with the transdermal deliverysystem. Blood samples were taken at frequent hour intervals on day 1 andday 7 in the group treated with orally delivered donepezil, and again ondays 8, 10, 12 and 14. Mean plasma concentration of donepezil in thetreatment groups are shown in FIGS. 2A-2B.

Example 5 In Vivo Administration of Donepezil from a DonepezilTransdermal Delivery System

Transdermal delivery systems comprising donepezil were prepared asdescribed in Example 2. Patients were enrolled and randomly separatedinto three treatment arms for a five week treatment study. The patientsin Arm 1 (n=52) and Arm 2 (n=51) were treated with a transdermal systemof Example 2, where the patients in Arm 1 wore a patch having a smallersurface area (Patch A) than the patients in Arm 2 (Patch B). Other thansize, Patch A and Patch B were identical. In the first week of thestudy, patients in Arm 1 and Arm 2 wore patches designed to deliver 5 mgdonepezil from a once-weekly patch. After the initial 7 day period, thepatients were given a transdermal system designed to be worn for 7 days(once-weekly transdermal patch) to deliver 10 mg donepezil per day,again with Patch A differing from Patch B only in surface area. Thetransdermal systems were replaced weekly for 4 weeks. The patients inArm 3 (n=54) were treated with a daily oral dose of 5 mg donepezil(ARICEPT) for 7 days followed by a once daily 10 mg dose of donepezil(ARICEPT) for 4 weeks.

For the subjects in Arm 1 and Arm 2, blood samples were taken dailyduring the fourth week of dosing at the 10 mg level, when plasmaconcentrations were at steady state. For the subjects in Arm 3, bloodsamples were taken on the last day of the fourth week of 10 mg/daydosing. The mean plasma concentration of donepezil for the treatmentarms in the fourth week of the 10 mg dosing are shown in FIG. 5A, wheresubjects treated with donepezil administered transdermally fromtransdermal Patch A (smaller surface area, solid line, transdermal PatchB (larger surface area, dashed line) and oral donepezil (thick, boldline at days 6-7) are shown, along with a dotted line showing theprojected daily plasma concentration for oral treatment.

FIG. 5B is a bar graph showing the number of gastrointestinal relatedadverse events (nausea, vomiting and diarrhea) reported by subjects inthe study, where bars with dashed fill correspond to subjects treatedwith the weekly smaller size transdermal patch, the bars with verticalline fill correspond to subjects treated with the weekly larger sizetransdermal patch, and the bars with horizontal line fill correspond tothe subjects treated with oral donepezil.

While a number of exemplary aspects and embodiments have been discussedabove, those of skill in the art will recognize certain modifications,permutations, additions and sub-combinations thereof. It is thereforeintended that the following appended claims and claims hereafterintroduced are interpreted to include all such modifications,permutations, additions and sub-combinations as are within their truespirit and scope.

It is claimed:
 1. A composition, comprising: a drug reservoir comprisedof a molar amount of donepezil HCl, an equimolar or less than equimolaramount of a pharmaceutically acceptable alkaline salt, a solventcomposition comprising a hydrophilic solvent, and an acrylate copolymer,wherein the alkaline salt is sodium bicarbonate or potassiumbicarbonate; and a skin contact adhesive comprising one or more of (i)triethyl citrate, (ii) sorbitan monolaurate, and (iii) lauryl lactate,wherein reaction of donepezil HCl and the alkaline salt generates atherapeutically effective amount of donepezil base in situ in the drugreservoir when the skin contact adhesive is attached to skin of asubject.
 2. The composition of claim 1, wherein the solvent compositioncomprises one or more of triethyl citrate, sorbitan monolaurate, andlauryl lactate.
 3. The composition of claim 1, wherein the solventcomposition comprises between about 8-12 wt % triethyl citrate, betweenabout 1.5-2.5 wt % sorbitan monolaurate, and between about 1-10 wt %lauryl lactate.
 4. The composition of claim 3, wherein the skin contactadhesive comprises between about 1-20 wt % triethyl citrate, betweenabout 0.01-5 wt % sorbitan monoloaurate, and between about 0.1-10 wt %lauryl lactate.
 5. The composition of claim 1, wherein the hydrophilicsolvent is selected from the group consisting of polyethylene glycol,propylene glycol, glycerin, acetonitrile, 1-propanol, andN,N-dimethylformamide.
 6. The composition of claim 1, wherein thehydrophilic solvent is glycerin.
 7. The composition of claim 6,comprising between about 5-15 wt % glycerin.
 8. The composition of claim1, comprising between about 1-5 wt % sodium bicarbonate.
 9. Thecomposition of claim 1, comprising between about 5-25 wt % donepezilHCl.
 10. A composition, comprising: a drug reservoir comprised of amolar amount of a donepezil salt, an equivalent or less than equivalentamount of a pharmaceutically acceptable alkaline salt, a solventcomposition comprising a hydrophilic solvent, and an acrylate copolymer,wherein the alkaline salt is sodium bicarbonate or potassiumbicarbonate; and a skin contact adhesive comprising one or more of (i)triethyl citrate, (ii) sorbitan monolaurate, and (iii) lauryl lactate,wherein reaction of the donepezil salt and the alkaline salt generates atherapeutically effective amount of donepezil base in situ in the drugreservoir when the skin contact adhesive is attached to skin of asubject.
 11. The composition of claim 10, wherein the solventcomposition comprises between about 8-12 wt % triethyl citrate, betweenabout 1.5-2.5 wt % sorbitan monolaurate, and between about 1-10 wt %lauryl lactate.
 12. The composition of claim 11, wherein the skincontact adhesive comprises between about 1-20 wt % triethyl citrate,between about 0.01-5 wt % sorbitan monoloaurate, and between about0.1-10 wt % lauryl lactate.
 13. The composition of claim 10, wherein thehydrophilic solvent is selected from the group consisting ofpolyethylene glycol, propylene glycol, glycerin, acetonitrile,1-propanol, and N,N-dimethylformamide.
 14. The composition of claim 10,wherein the hydrophilic solvent is glycerin.
 15. The composition ofclaim 14, comprising between about 5-15 wt % glycerin.
 16. Thecomposition of claim 10, comprising between about 1-5 wt % sodiumbicarbonate.
 17. The composition of claim 10, wherein the donepezil saltis donepezil HCl.
 18. The composition of claim 17, comprising betweenabout 5-25 wt % donepezil HCl.